TLR4 and chronic obstructive pulmonary disease: Crucially, in habitual smokers and smokers with COPD, there is a downregulation of airway epithelial TLR expression, particularly of TLR5, which binds bacterial flagellin, as well as disturbance of TLR2 and TLR4 signaling, all contributing to the increased sensitivity to infections in COPD (95, 96).